Cyclosporin A, but not FK506 induces osmotic lysis of pancreas zymogen granules (ZG), intra‐acinar enzyme release and lysosome instability by activating a K+ channel

Abstract

The immunosuppressant tacrolimus (FK506) has improved pancreas allograft survival compared to cyclosporin A (CsA), possibly due to reduced acute pancreatitis following ischemia‐reperfusion injury. Ion permeabilities in zymogen granules (ZG) membranes, including a KCNQ1 K+ channel, promote hormone‐stimulated enzyme secretion. We investigated whether a differential modulation of ZG and lysosomal ion permeabilities, and enzyme secretion by CsA/FK506 contributes to pancreatitis. Rat ZG and lysosomes were isolated by gradient centrifugation, ion permeabilities assayed by osmotic lysis, and single channel currents recorded in a planar lipid bilayer. Amylase release was measured in permeabilized acini and lysosomal cathepsin B release detected by immunoblotting. CsA (1–10μM), but not FK506, enhanced ZG osmotic lysis by selectively increasing K+ permeability up to 5‐fold. ZG membrane K+ channels showed ~2‐fold increased single channel open probability with CsA only. CsA selectively increased basal (~2‐fold), but not cholecystokinin‐octapeptide (1nM)‐induced amylase secretion in K+ medium only. CsA (5μM), but not FK506, increased cathepsin B release from lysosomes. CsA selectively opens the ZG K+channel and induces cathepsin B release from lysosomes, which cause increased in situ lysis of ZG and may induce or aggravate acute allograft pancreatitis. Funded by Mukoviszidose e.V. (F 04/04) and DFG TH 345/11‐1.